nach oben

Erschienen in:

01.05.2015 | Original article

Mitochondrial tRNA glutamine variant in hypertrophic cardiomyopathy

verfasst von: S. Zarrouk-Mahjoub, S. Mehri, F. Ouarda, J. Finsterer, MD, PhD, R. Boussaada

Erschienen in: Herz | Ausgabe 3/2015

Einloggen, um Zugang zu erhalten

Abstract

Background

Mitochondria play critical roles in both the life and death of cardiac myocytes. Pathogenic mitochondrial DNA (mtDNA) mutations leading to mitochondrial dysfunction can cause cardiomyopathies (CMPs). Our aim was to investigate the underlying mitochondrial defect in a patient with hypertrophic cardiomyopathy (hCMP). A detailed clinical and molecular genetic analysis was performed.

Patients and methods

Total DNA was extracted from lymphocytes in a 14-year-old index male patient with hCMP, preexcitation syndrome, and severe ventricular arrhythmias. Direct sequencing of the PCR fragments was performed. To distinguish deleterious from functionally neutral variants, the ClustalW program, RNAfold software, and PolyPhen algorithm were applied, which predict the pathogenicity of a particular variant by using a set of empirical rules based on the nature of the mutation, the phylogenetic conservation of the variant, and the physicochemical property of the amino acid.

Results

The mutational analysis of mtDNA genes revealed four variants. The m.4395A>G transition (C6G) in the MT-TQ gene, which altered an evolutionary conserved nucleotide, with a conservation index of 85.7 % and affected a highly conserved U.G base pair in the secondary structure of MT-TQ. Additionally, the previously reported polymorphisms m.14757T>A, m.15236A>G, and m.15314G>A resulting in the replacement of amino acid residues in the MT-CYB gene were detected.

Conclusion

The m.4395A>G variant was scored as possibly pathogenic and may exert a negative effect on heart function to generate hCMP.

Klues HG, Schiffers A, Maron BJ (1995) Phenotypic spectrum and patterns of left ventricular hypertrophy in hypertrophic cardiomyopathy: morphologic observations and significance as assessed by two dimensional echocardiography in 600 patients. J Am Coll Cardiol 26:1699–1708CrossRefPubMed

Levinger L, Mörl M, Florentz C (2004) Mitochondrial tRNA 3’ end metabolism and human disease. Nucleic Acids Res 32:5430–5441CrossRefPubMedCentralPubMed

Taylor RW, Giordano C, Davidson MM et al (2003) Homoplasmic mitochondrial transfer ribonucleic acid mutation as a cause of maternally inherited hypertrophic cardiomyopathy. J Am Coll Cardiol 41:1786–1796CrossRefPubMed

Maron BJ, Gardin JM, Flack JM et al (1995) Prevalence of hypertrophic cardiomyopathy in a general population of young adults: echocardiographic analysis of 4111 subjects in the CARDIA Study. Coronary artery risk development in (Young) adults. Circulation 92:785–789CrossRefPubMed

Maron BJ, Moller JH, Seidman CE et al (1998) Impact of laboratory molecular diagnosis on contemporary diagnostic criteria for genetically transmitted cardiovascular diseases: hypertrophic cardiomyopathy, long-QT syndrome, and Marfan syndrome. A statement for healthcare professionals from the Councils on Clinical Cardiology, Cardiovascular Disease in the Young, and Basic Science, American Heart Association. Circulation 98:1460–1471CrossRef

Niimura H, Bachinski LL, Sangwatanaroj S et al (1998) Mutations in the gene for human cardiac myosinbinding protein C and late-onset familial hypertrophic cardiomyopathy. N Engl J Med 338:1248–1257CrossRefPubMed

Marian AJ (2000) Pathogenesis of diverse clinical and pathological phenotypes in hypertrophic cardiomyopathy. Lancet 355:58–60CrossRefPubMed

Marin-Garciaa J, Goldenthala MJ, Moe GW (2001) Mitochondrial pathology in cardiac failure. Cardiovasc Res 49:17–26CrossRef

Sternberg D, Danan C, Lombès A et al (1998) Exhaustive scanning approach to screen all the mitochondrial tRNA genes for mutations and its application to the investigation of 35 independent patients with mitochondrial disorders. Hum Mol Genet 7:33–42CrossRefPubMed

10.

Thompson JD, Higgins DG, Gibson TJ (1994) Improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. Nucleic Acids Res 22:4673–4680CrossRefPubMedCentralPubMed

11.

Ruiz-Pesini E, Wallace DC (2006) Evidence for adaptive selection acting on the tRNA and rRNA genes of human mitochondrial DNA. Hum Mutat 27:1072–1081CrossRefPubMed

12.

Hofacker IL (2003) Vienna RNA secondary structure server. Nucleic Acids Res 31:3429–3431CrossRefPubMedCentralPubMed

13.

Scaglia F, Wong JC (2008) Human mitochondrial transfer RNAs: role of pathogenic mutation in disease. Muscle Nerve 37:150–171CrossRefPubMed

14.

Sunyaev S, Ramensky V, Koch I et al (2001) Prediction of deleterious human alleles. Hum Mol Genet 10:591–597CrossRefPubMed

15.

Schimmel P (1979) Similarities in the structural organization of complexes of tRNAs with aminoacyl-tRNA synthetases and the mechanism of recognition. In: Schimmel P et al (eds) Transfer RNA: structure, properties, and recognition. Cold Springs Harbor, pp 297–310.6

16.

Chomyn A et al (1992) MELAS mutation in mtDNA binding site for transcription termination factor causes defects in protein synthesis and in respiration but no change in levels of upstream and downstream mature transcripts. Proc Natl Acad Sci U S A 89:4221–4225CrossRefPubMedCentralPubMed

17.

Levinger L et al (2003) Pathology-related substitutions in human mitochondrial tRNA^Ile reduce precursor 3’ end processing efficiency in vitro. Nucleic Acids Res 31:1904–1912CrossRefPubMedCentralPubMed

18.

Levinger L et al (2001) In vitro 3’-end endonucleolytic processing defect in a human mitochondrial tRNA^Ser(UCN) precursor with the U7445C substitution, which causes non-syndromic deafness. Nucleic Acids Res 29:4334–4340CrossRefPubMedCentralPubMed

19.

Kelley SO et al (2000) Functional defects of pathogenic human mitochondrial tRNAs related to structural fragility. Nat Struct Biol 7:862–865CrossRefPubMed

20.

Degoul F et al (1998) Isoleucylation properties of native human mitochondrial tRNA^Ile and tRNA^Ile transcripts. Implications for cardiomyopathy-related point mutations (4269, 4317) in the tRNA^Ile gene. Hum Mol Genet 7:347–354CrossRefPubMed

21.

Ruiz-Pesini E, Lott MT, Procaccio V et al (2007) An enhanced MITOMAP with a global mtDNA mutational phylogeny. Nucleic Acids Research 35 (Database issue):D823-D828. http://www.mitomap.org

22.

Helm M, Brule H, Friede D et al (2000) Search for characteristic structural features of mammalian mitochondrial tRNAs. RNA 6:1356–1379CrossRefPubMedCentralPubMed

23.

Francisci S, De Luca C, Oliva R et al (2005) Aminoacylation and conformational properties of yeast mitochondrial tRNA mutants with respiratory deficiency. RNA 11:914–927CrossRefPubMedCentralPubMed

24.

Francisci S, Bohn C, Frontali L, Bolotin-Fukuhara M (1998) Ts mutations in mitochondrial tRNA genes: Characterization and effects of two point mutations in the mitochondrial gene for tRNAPhe in Saccharomyces cerevisiae. Curr Genet 33:110–116CrossRefPubMed

25.

Feuermann M, Francisci S, Rinaldi T et al (2003) The yeast counterparts of human ‘MELAS’ mutations cause mitochondrial dysfunction that can be rescued by overexpression of the mitochondrial translation factor EF-Tu. EMBO Rep 4:53–58CrossRefPubMedCentralPubMed

26.

Zhu HY, Wang SW, Liu L et al (2009) Genetic variants in mitochondrial tRNA genes are associated with essential hypertension in a Chinese Han population. Clin Chim Acta 410(1–2):64–69

27.

Tsujita Y, Kunitomo T, Fujii M et al (2008) A surviving case of mitochondrial cardiomyopathy diagnosed from the symptoms of multiple organ dysfunction syndrome. Int J Cardiol 128:e43–e45CrossRefPubMed

28.

Zeviani M, Gellera C, Antozzi C et al (1991) Maternally inherited myopathy and cardiomyopathy: association with mutation in mitochondrial DNA tRNA(Leu)(UUR). Lancet 338:143–147CrossRefPubMed

29.

Silvestri G, Santorelli FM, Shanske S et al (1994) A new mtDNA mutation in the tRNA(Leu(UUR)) gene associated with maternally inherited cardiomyopathy. Hum Mutat 3:37–43CrossRefPubMed

30.

Grasso M, Diegoli M, Brega A et al (2001) The mitochondrial DNA mutation T12297C affects a highly conserved nucleotide of tRNA(Leu(CUN)) and is associated with dilated cardiomyopathy. Eur J Hum Genet 9:311–315CrossRefPubMed

31.

Taniike M, Fukushima H, Yanagihara I et al (1992) Mitochondrial tRNAIle in fatal cardiomyopathy. Biochem Biophys Res Commun 186:47–53CrossRefPubMed

32.

Mahjoub S, Sternberg D, Boussaada R et al (2007) A novel mitochondrial DNA tRNA Ile (m.4322dupC) mutation associated with idiopathic dilated cardiomyopathy. Diagn Mol Pathol 16:238–242CrossRefPubMed

33.

Akita Y, Koga Y, Iwanaga R et al (2000) Fatal hypertrophic cardiomyopathy associated with an A8296G mutation in the mitochondrial tRNA(Lys) gene. Hum Mutat 15:382CrossRefPubMed

34.

Hattori Y, Takeoka M, Nakajima K et al (2005) A heteroplasmic mitochondrial DNA 3310 mutation in the ND1 gene in a patient with type 2 diabetes, hypertrophic cardiomyopathy, and mental retardation. Exp Clin Endocrinol Diabetes 113:318–323CrossRefPubMed

35.

Taylor RW, Giordano C, Davidson MM et al (2003) A homoplasmic mitochondrial transfer ribonucleic acid mutation as a cause of maternally inherited hypertrophic cardiomyopathy. J Am Coll Cardiol 41:1786–1796CrossRefPubMed

36.

Shin WS, Tanaka M, Suzuki J et al (2000) A novel homoplasmic mutation in mtDNA with a single evolutionary origin as a risk factor for cardiomyopathy. Am J Hum Genet 67:1617–1620CrossRefPubMedCentralPubMed

37.

Prezant TR, Agapian JV, Bohlman MC et al (1993) Mitochondrial ribosomal RNA mutation associated with both antibiotic-induced and non-syndromic deafness. Nat Genet 4:289–294CrossRefPubMed

38.

Sue CM, Tanji K, Hadjigeorgiou G et al (1999) Maternally-inherited hearing loss in a large kindred with a novel T7511C mutation in the mitochondrial DNA tRNASer(UCN) gene. Neurology 52:1905–1908CrossRefPubMed

39.

DiMauro S, Schon EA (2001) Mitochondrial DNA mutations in human disease. Am J Med Genet 6:18–26CrossRef

40.

Ware SM, El-Hassan N, Kahler SG et al (2009) Infantile cardiomyopathy caused by a mutation in the overlapping region of mitochondrial ATPase 6 and 8 genes. J Med Genet 46(5):308–314CrossRefPubMed

41.

Zhou X, Zhang H, Zhao F et al (2010) Very high penetrance and occurrence of Leber’s hereditary optic neuropathy in a large Han Chinese pedigree carrying the ND4 G11778A mutation. Mol Genet Metab 100(4):379–384CrossRefPubMedCentralPubMed

Titel: Mitochondrial tRNA glutamine variant in hypertrophic cardiomyopathy
verfasst von: S. Zarrouk-Mahjoub
S. Mehri
F. Ouarda
J. Finsterer, MD, PhD
R. Boussaada
Publikationsdatum: 01.05.2015
Verlag: Urban & Vogel
Erschienen in: Herz / Ausgabe 3/2015
Print ISSN: 0340-9937
Elektronische ISSN: 1615-6692
DOI: https://doi.org/10.1007/s00059-013-3950-8

Neu im Fachgebiet Kardiologie

25.04.2024 | Hypotonie | Nachrichten

Update Kardiologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Springer Medizin

Mitochondrial tRNA glutamine variant in hypertrophic cardiomyopathy

Abstract

Background

Patients and methods

Results

Conclusion

Neu im Fachgebiet Kardiologie

Niedriger diastolischer Blutdruck erhöht Risiko für schwere kardiovaskuläre Komplikationen

Therapiestart mit Blutdrucksenkern erhöht Frakturrisiko

Adipositas-Medikament auch gegen Schlafapnoe wirksam

Komplette Revaskularisation bei Infarkt: Neue Studie setzt ein Fragezeichen

Update Kardiologie

Springer Medizin

Abstract

Background

Patients and methods

Results

Conclusion

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 3/2015

Are we aware of stent fracture?

Plötzlicher Herztod bei Sportlern und dessen Prävention

Genetic association of IL-21 polymorphisms with dilated cardiomyopathy in a Han Chinese population

Hypertonic saline plus i.v. furosemide improve renal safety profile and clinical outcomes in acute decompensated heart failure

Kardiovaskuläre Schäden durch Doping

Acute myocardial infarction after a gunshot wound

Neu im Fachgebiet Kardiologie

Niedriger diastolischer Blutdruck erhöht Risiko für schwere kardiovaskuläre Komplikationen

Therapiestart mit Blutdrucksenkern erhöht Frakturrisiko

Adipositas-Medikament auch gegen Schlafapnoe wirksam

Komplette Revaskularisation bei Infarkt: Neue Studie setzt ein Fragezeichen

Update Kardiologie